We have advanced many lines of evidence indicating that the clinical and biochemical manifestations of melancholic depression reflect a concomitant activation of the corticotropin releasing hormone and locus ceruleus-norepinephrine systems that have escaped their usual counter- regulatory mechanisms. Recent data supporting this hypothesis derives from our studies of the 30-hour pattern of neurohormones and neurotransmitters into the CSF of patients with depression and controls studied by continuous lumbar CSF drainage. These data show significant increases in secretory episodes and integrated concentrations of both CSF CRH and norepinephrine in melancholia. In laboratory animals, we have shown that lesioning of the paraventricular nucleus results in a greater than 60% fall in the concentrations of CRH in the CSF. These data indicating that the hypothalamus is a principal source for both hypophyseal and CSF concentrations of CRH are compatible with our data showing hypercortisolism and increased concentrations of CRH in the CSF of melancholic patients and suggest that paraventricular nucleus CRH may contribute both to the pituitary-adrenal activation, inhibition of vegetative functions, and hyperarousal characteristic of melancholic depression. We have extended our data regarding tricyclic anti- depressants and MAO inhibitors to other less typical antidepressants showing that all known effective antidepressants, regardless of their putative mode of action, significantly decrease CRH mRNA content in the hypothalamus of the rat after chronic administration. In further studies exploring the role of acute and chronic glucocorticoid secretion during stress, we have demonstrated that the acute and chronic administration of dexamethasone to the rat increases CRH mRNA and content in the central nucleus of the amygdala, in contrast to its effect on decreasing these parameters in the paraventricular nucleus of the hypothalamus. These data indicate that while it is adaptive for glucocorticoids to acutely and chronically restrain the effects of CRH to inhibit vegetative functions so that chronic stress is not associated with sustained anorexia and inhibition of reproductive function, chronic stress, via the glucocorticoids, acts to enhance the arousal producing effects of CRH that are thought to occur principally at the central nucleus of the amygdala.